Radiation exposure from a nuclear accident or potential terrorist attack can cause death from acute injury or from late effects of radiation. Studies of the survivors of the atomic bomb at Hiroshima reveal that many radiation-induced deaths occurred years after the exposure. Some medical treatments are available or are under development to treat the acute radiation syndrome. Because radiation causes apoptosis of some cell types, blocking apoptosis may limit acute radiation injury. In contrast, no effective countermeasures exist to mitigate the late effects of radiation exposure. Furthermore, it is not clear how interventions that prevent the acute radiation syndrome, such as blocking radiation-induced apoptosis, may alter the spectrum of late effects years after radiation exposure. For example, it is conceivable that blocking apoptosis to limit acute injury could inadvertently increase late morbidity and mortality from radiation. In this proposal, we will use sophisticated mouse genetics to dissect the mechanisms of radiation-induced carcinogenesis and vascular injury following a single exposure to radiation. Moreover, we will determine the long-term sequellae of blocking radiation-induced apoptosis. The ultimate objective of these studies will be to provide a foundation of pre-clinical data to develop safe and effective medical products to prevent acute and late effects of radiation. In this proposal we will use mouse genetics to determine whether temporary inhibition of p53 or the intrinsic pathway of apoptosis exacerbates late effects of radiation such as radiation-induced cancers and vascular injury. These in vivo studies will provide a mechanistic foundation for the design of safe and effective countermeasures against radiation that do not inadvertently increase late effects of radiation.